1-24652438-A-G

Variant names:

• chr1-24652438-A-G
• rs377349401
• NM_005839.4:c.730A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005839.4(SRRM1):​c.730A>G​(p.Ile244Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000194 in 1,549,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. I244F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: SRRM1 NM_005839.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.73
• Publications: 1 publications found

Genes affected

SRRM1 (HGNC:16638): (serine and arginine repetitive matrix 1) Enables RNA binding activity. Predicted to be involved in mRNA splicing, via spliceosome. Located in nuclear speck. Part of catalytic step 2 spliceosome. Biomarker of gestational diabetes. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12225059).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005839.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRRM1	NM_005839.4	MANE Select	c.730A>G	p.Ile244Val	missense	Exon 7 of 17	NP_005830.2
	SRRM1	NM_001366595.1		c.730A>G	p.Ile244Val	missense	Exon 7 of 18	NP_001353524.1	A0A0S2Z4Z6
	SRRM1	NM_001366569.1		c.730A>G	p.Ile244Val	missense	Exon 7 of 18	NP_001353498.1	A0A994J7V4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRRM1	ENST00000323848.14	TSL:1 MANE Select	c.730A>G	p.Ile244Val	missense	Exon 7 of 17	ENSP00000326261.8	Q8IYB3-1
	SRRM1	ENST00000596378.1	TSL:1	c.613A>G	p.Ile205Val	missense	Exon 7 of 15	ENSP00000471084.1	M0R088
	SRRM1	ENST00000928582.1		c.730A>G	p.Ile244Val	missense	Exon 7 of 19	ENSP00000598641.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151858 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000484 AC: 1 AN: 206722 AF XY: 0.00

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: 0.00000997

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1397184 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 693604

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

African (AFR) AF: 0.00 AC: 0 AN: 29774

American (AMR) AF: 0.00 AC: 0 AN: 31148

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23590

East Asian (EAS) AF: 0.00 AC: 0 AN: 38284

South Asian (SAS) AF: 0.00 AC: 0 AN: 75464

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51996

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4024

European-Non Finnish (NFE) AF: 9.21e-7 AC: 1 AN: 1085624

Other (OTH) AF: 0.00 AC: 0 AN: 57280

⚠️ 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.

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151858 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74226

African (AFR) AF: 0.00 AC: 0 AN: 41352

American (AMR) AF: 0.00 AC: 0 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10540

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67954

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.46	N
PhyloP100		4.7
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.050
Sift	Benign	0.055	T
Sift4G	Benign	0.51	T
Polyphen		0.0	B
Vest4		0.26
MVP		0.16
MPC		0.31
ClinPred		0.26	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.22
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs377349401; hg19: chr1-24978929; COSMIC: COSV100105324; COSMIC: COSV100105324;