NM_015077.4:c.*2442T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_015077.4(SARM1):c.*2442T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.537 in 152,180 control chromosomes in the GnomAD database, including 22,259 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.54 ( 22239 hom., cov: 33)

Exomes 𝑓: 0.60 ( 20 hom. )

Consequence

SARM1
NM_015077.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.891

Publications

27 publications found

Variant links:

Genes affected

SARM1 (HGNC:17074): (sterile alpha and TIR motif containing 1) Enables NAD+ nucleotidase, cyclic ADP-ribose generating and identical protein binding activity. Involved in NAD catabolic process; positive regulation of neuron death; and response to axon injury. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

SARM1 links:

SLC46A1 (HGNC:30521): (solute carrier family 46 member 1) This gene encodes a transmembrane proton-coupled folate transporter protein that facilitates the movement of folate and antifolate substrates across cell membranes, optimally in acidic pH environments. This protein is also expressed in the brain and choroid plexus where it transports folates into the central nervous system. This protein further functions as a heme transporter in duodenal enterocytes, and potentially in other tissues like liver and kidney. Its localization to the apical membrane or cytoplasm of intestinal cells is modulated by dietary iron levels. Mutations in this gene are associated with autosomal recessive hereditary folate malabsorption disease. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Aug 2013]

SLC46A1 Gene-Disease associations (from GenCC):

hereditary folate malabsorption
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics

SLC46A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 17-28398728-T-C is Benign according to our data. Variant chr17-28398728-T-C is described in ClinVar as Benign. ClinVar VariationId is 322393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.707 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SARM1	NM_015077.4 link	c.*2442T>C		3_prime_UTR_variant	Exon 9 of 9	ENST00000585482.6	NP_055892.2	Q6SZW1-1Q05B42Q0D2N8
SLC46A1	NM_080669.6 link	c.*928A>G		3_prime_UTR_variant	Exon 5 of 5	ENST00000612814.5	NP_542400.2	Q96NT5-1A0A024QZ15

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
SARM1	ENST00000585482.6 link	c.*2442T>C	3_prime_UTR_variant	Exon 9 of 9	1	NM_015077.4	ENSP00000468032.2	Q6SZW1-1
SLC46A1	ENST00000612814.5 link	c.*928A>G	3_prime_UTR_variant	Exon 5 of 5	2	NM_080669.6	ENSP00000480703.1	Q96NT5-1
SLC46A1	ENST00000618626.1 link	c.*928A>G	3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000483652.1	Q96NT5-2

Frequencies

GnomAD3 genomes

AF:

0.537

AC:

81636

AN:

151966

Hom.:

22249

Cov.:

show subpopulations

Gnomad AFR

AF:

0.476

Gnomad AMI

AF:

0.549

Gnomad AMR

AF:

0.612

Gnomad ASJ

AF:

0.566

Gnomad EAS

AF:

0.726

Gnomad SAS

AF:

0.536

Gnomad FIN

AF:

0.434

Gnomad MID

AF:

0.671

Gnomad NFE

AF:

0.556

Gnomad OTH

AF:

0.582

GnomAD4 exome

AF:

0.604

AC:

AN:

Hom.:

Cov.:

AF XY:

0.611

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.500

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

AN:

East Asian (EAS)

AF:

1.00

AC:

AN:

South Asian (SAS)

AF:

0.500

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

1.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.635

AC:

AN:

Other (OTH)

AF:

0.167

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.537

AC:

81653

AN:

152084

Hom.:

22239

Cov.:

AF XY:

0.533

AC XY:

39606

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.475

AC:

19700

AN:

41446

American (AMR)

AF:

0.613

AC:

9369

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.566

AC:

1965

AN:

3472

East Asian (EAS)

AF:

0.727

AC:

3768

AN:

5184

South Asian (SAS)

AF:

0.535

AC:

2577

AN:

4820

European-Finnish (FIN)

AF:

0.434

AC:

4589

AN:

10570

Middle Eastern (MID)

AF:

0.660

AC:

194

AN:

294

European-Non Finnish (NFE)

AF:

0.556

AC:

37771

AN:

67988

Other (OTH)

AF:

0.579

AC:

1220

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1976

3951

5927

7902

9878

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

714

1428

2142

2856

3570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.561

Hom.:

22789

Bravo

AF:

0.551

Asia WGS

AF:

0.556

AC:

1934

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital defect of folate absorption

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

5.2

(source)

DANN

Benign

0.73

PhyloP100

0.89

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over