dbSNP rs299295: HMMR:p.Ala485Glu (chr5-163482710-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001142556.2(HMMR):c.1454C>A(p.Ala485Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A485T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

HMMR
NM_001142556.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.30

Publications

32 publications found

Variant links:

Genes affected

HMMR (HGNC:5012): (hyaluronan mediated motility receptor) The protein encoded by this gene is involved in cell motility. It is expressed in breast tissue and together with other proteins, it forms a complex with BRCA1 and BRCA2, thus is potentially associated with higher risk of breast cancer. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Dec 2008]

HMMR links:

HMMR-AS1 (HGNC:49149): (HMMR antisense RNA 1)

HMMR-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.064680785).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142556.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HMMR	NM_001142556.2	MANE Select	c.1454C>A	p.Ala485Glu	missense	Exon 13 of 18	NP_001136028.1	O75330-3
HMMR	NM_012484.3		c.1451C>A	p.Ala484Glu	missense	Exon 13 of 18	NP_036616.2	O75330-1
HMMR	NM_012485.3		c.1406C>A	p.Ala469Glu	missense	Exon 12 of 17	NP_036617.2	O75330-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HMMR	ENST00000393915.9	TSL:1 MANE Select	c.1454C>A	p.Ala485Glu	missense	Exon 13 of 18	ENSP00000377492.4	O75330-3
HMMR	ENST00000358715.3	TSL:1	c.1451C>A	p.Ala484Glu	missense	Exon 13 of 18	ENSP00000351554.3	O75330-1
HMMR	ENST00000353866.7	TSL:1	c.1406C>A	p.Ala469Glu	missense	Exon 12 of 17	ENSP00000185942.6	O75330-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251072

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460690

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726706

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33454

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1110926

Other (OTH)

AF:

0.00

AC:

AN:

60376

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.24

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.29

M_CAP

Benign

0.0073

MetaRNN

Benign

0.065

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

2.3

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.50

REVEL

Benign

0.067

Sift

Uncertain

0.012

Sift4G

Benign

0.98

Polyphen

0.0070

Vest4

0.15

MutPred

0.23

Gain of ubiquitination at K486 (P = 0.0483)

MVP

0.35

MPC

0.070

ClinPred

0.19

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.063

gMVP

0.49

Mutation Taster

=98/2

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over