rs200590643

Variant names:

• chr19-43612556-A-G
• rs200590643
• NM_001145641.2:c.435A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001145641.2(SRRM5):​c.435A>G​(p.Ile145Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000694 in 1,551,510 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I145V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00065 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (4 hom.)
• Consequence: SRRM5 NM_001145641.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0110

Genes affected

SRRM5 (HGNC:37248): (serine/arginine repetitive matrix 5)

ZNF428 (HGNC:20804): (zinc finger protein 428) Predicted to enable metal ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014071614).
• BP6: Variant 19-43612556-A-G is Benign according to our data. Variant chr19-43612556-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2350665.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRRM5	NM_001145641.2	c.435A>G	p.Ile145Met	missense_variant	Exon 1 of 1	ENST00000417606.3	NP_001139113.1
ZNF428	NM_182498.4	c.76+1673T>C		intron_variant	Intron 2 of 2	ENST00000300811.8	NP_872304.2
ZNF428	XM_047438168.1	c.76+1673T>C		intron_variant	Intron 3 of 3		XP_047294124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRRM5	ENST00000417606.3	c.435A>G	p.Ile145Met	missense_variant	Exon 1 of 1	6	NM_001145641.2	ENSP00000414512.1
ZNF428	ENST00000300811.8	c.76+1673T>C		intron_variant	Intron 2 of 2	1	NM_182498.4	ENSP00000300811.2
SRRM5	ENST00000607544.1	c.435A>G	p.Ile145Met	missense_variant	Exon 3 of 3	2		ENSP00000476253.1
ZNF428	ENST00000598676.1	c.76+1673T>C		intron_variant	Intron 2 of 3	5		ENSP00000469484.1

Frequencies

GnomAD3 genomes AF: 0.000651 AC: 99 AN: 152004 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000897

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000610 AC: 94 AN: 153974 AF XY: 0.000746

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000729

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000656

Gnomad NFE exome AF: 0.000989

Gnomad OTH exome AF: 0.00138

GnomAD4 exome AF: 0.000698 AC: 977 AN: 1399388 Hom.: 4 Cov.: 30 AF XY: 0.000719 AC XY: 496 AN XY: 690202

African (AFR) AF: 0.0000316 AC: 1 AN: 31598

American (AMR) AF: 0.000616 AC: 22 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.000404 AC: 32 AN: 79236

European-Finnish (FIN) AF: 0.0000406 AC: 2 AN: 49260

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5698

European-Non Finnish (NFE) AF: 0.000824 AC: 889 AN: 1078966

Other (OTH) AF: 0.000517 AC: 30 AN: 58006

GnomAD4 genome AF: 0.000651 AC: 99 AN: 152122 Hom.: 2 Cov.: 32 AF XY: 0.000686 AC XY: 51 AN XY: 74376

African (AFR) AF: 0.000217 AC: 9 AN: 41504

American (AMR) AF: 0.00177 AC: 27 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000897 AC: 61 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000738 Hom.: 1

Bravo AF: 0.000703

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000723 AC: 1

ESP6500EA AF: 0.000629 AC: 2

ExAC AF: 0.000153 AC: 4

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jun 10, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	6.9
DANN	Benign	0.93
DEOGEN2	Benign	0.0011	T;T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.32	.;T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
PhyloP100		0.011
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.38	.;N
REVEL	Benign	0.020
Sift	Benign	0.043	.;D
Sift4G	Benign	0.11	T;T
Polyphen		0.025	B;B
Vest4		0.034
MVP		0.014
MPC		0.014
ClinPred		0.026	T
GERP RS		-0.41
PromoterAI		0.012	Neutral
Varity_R		0.081
gMVP		0.016
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs200590643; hg19: chr19-44116708;