1-108877219-C-T

Variant names:

• chr1-108877219-C-T
• rs35520362
• NM_013296.5:c.-258C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_013296.5(GPSM2):​c.-258C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0932 in 152,204 control chromosomes in the GnomAD database, including 708 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.093 (708 hom., cov: 31)
  • Exomes 𝑓: 0.033 (0 hom.)
• Consequence: GPSM2 NM_013296.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0500
• Publications: 6 publications found

Genes affected

GPSM2 (HGNC:29501): (G protein signaling modulator 2) The protein encoded by this gene belongs to a family of proteins that modulate activation of G proteins, which transduce extracellular signals received by cell surface receptors into integrated cellular responses. The N-terminal half of this protein contains 10 copies of leu-gly-asn (LGN) repeat, and the C-terminal half contains 4 GoLoco motifs, which are involved in guanine nucleotide exchange. This protein may play a role in neuroblast division and in the development of normal hearing. Mutations in this gene are associated with autosomal recessive nonsyndromic deafness (DFNB82). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

AKNAD1 (HGNC:28398): (AKNA domain containing 1) This gene encodes a protein which contains a domain found in an AT-hook-containing transcription factor. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2012]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 1-108877219-C-T is Benign according to our data. Variant chr1-108877219-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 291698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013296.5. 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
	GPSM2	NM_013296.5	MANE Select	c.-258C>T		5_prime_UTR	Exon 1 of 15	NP_037428.3
	GPSM2	NM_001321038.2		c.-26C>T		5_prime_UTR	Exon 1 of 15	NP_001307967.1	P81274
	GPSM2	NM_001321039.3		c.-258C>T		5_prime_UTR	Exon 1 of 16	NP_001307968.1	P81274

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPSM2	ENST00000264126.9	TSL:1 MANE Select	c.-258C>T		5_prime_UTR	Exon 1 of 15	ENSP00000264126.3	P81274
	GPSM2	ENST00000674914.1		c.-69C>T		5_prime_UTR	Exon 1 of 16	ENSP00000501579.1	A0A6Q8PF02
	GPSM2	ENST00000675087.1		c.-219C>T		5_prime_UTR	Exon 1 of 17	ENSP00000502020.1	A0A6Q8PF02

Frequencies

GnomAD3 genomes AF: 0.0932 AC: 14166 AN: 151998 Hom.: 708 Cov.: 31

Gnomad AFR AF: 0.0966

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.0677

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.000581

Gnomad SAS AF: 0.0641

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.0866

GnomAD4 exome AF: 0.0333 AC: 3 AN: 90 Hom.: 0 Cov.: 0 AF XY: 0.0455 AC XY: 3 AN XY: 66

⚠️ 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: 2

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0366 AC: 3 AN: 82

Other (OTH) AF: 0.00 AC: 0 AN: 4

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0628932), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0932 AC: 14180 AN: 152114 Hom.: 708 Cov.: 31 AF XY: 0.0919 AC XY: 6834 AN XY: 74370

African (AFR) AF: 0.0967 AC: 4015 AN: 41520

American (AMR) AF: 0.0676 AC: 1034 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 385 AN: 3472

East Asian (EAS) AF: 0.000583 AC: 3 AN: 5150

South Asian (SAS) AF: 0.0648 AC: 312 AN: 4816

European-Finnish (FIN) AF: 0.110 AC: 1161 AN: 10594

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.103 AC: 6971 AN: 67946

Other (OTH) AF: 0.0857 AC: 181 AN: 2112

Alfa AF: 0.0798 Hom.: 200

Bravo AF: 0.0883

Asia WGS AF: 0.0320 AC: 112 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Chudley-McCullough syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	7.8
DANN	Benign	0.77
PhyloP100		-0.050
PromoterAI		0.045	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35520362; hg19: chr1-109419841;