14-106537943-C-G

Variant names:

• chr14-106537943-C-G
• rs7148607
• ENST00000390624.3:c.220G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000390624.3(IGHV3-48):​c.220G>C​(p.Gly74Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 4/5 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000016 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: IGHV3-48 ENST00000390624.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.59
• Publications: 5 publications found

Genes affected

IGHV3-48 (HGNC:5606): (immunoglobulin heavy variable 3-48) Predicted to enable antigen binding activity and immunoglobulin receptor binding activity. Predicted to be involved in several processes, including activation of immune response; defense response to other organism; and phagocytosis. Predicted to be located in extracellular region and plasma membrane. Predicted to be part of immunoglobulin complex, circulating. Predicted to be active in external side of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

IGH (HGNC:5477):

ACMG classification

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 (BayesDel_noAF=-0.87).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGHV3-48	unassigned_transcript_2596	c.220G>C	p.Gly74Arg	missense_variant	Exon 2 of 2
IGH		n.106537943C>G		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGHV3-48	ENST00000390624.3	c.220G>C	p.Gly74Arg	missense_variant	Exon 2 of 2	6		ENSP00000375033.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000160 AC: 1 AN: 625314 Hom.: 0 Cov.: 0 AF XY: 0.00000293 AC XY: 1 AN XY: 340744

⚠️ 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: 17642

American (AMR) AF: 0.00 AC: 0 AN: 43590

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20804

East Asian (EAS) AF: 0.00 AC: 0 AN: 35926

South Asian (SAS) AF: 0.00 AC: 0 AN: 69616

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52934

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4104

European-Non Finnish (NFE) AF: 0.00000287 AC: 1 AN: 347870

Other (OTH) AF: 0.00 AC: 0 AN: 32828

⚠️ 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 Cov.: 31

Alfa AF: 0.00 Hom.: 3933

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_noAF	Benign	-0.87
CADD	Benign	8.4
PhyloP100		-1.6

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: rs7148607; hg19: chr14-106993945;